Project Summary Males and females differ in their basic physiology and pathophysiology in essentially all physiological systems. These biological sex differences can lead to differences in disease prevalence, progression rates and treatment outcomes. Understanding these differences can serve to identify new disease mechanisms and/or new and improved therapeutic opportunities. Thus, there is an immense need for additional research into the area of sex differences in both animal models and people. Acid-base homeostasis is of critical importance for maintaining normal health and renal ammonia metabolism has a major role in the maintenance of acid-base homeostasis. I have shown there are significant sex differences in basal ammonia excretion that result from sex differences in the expression of multiple important proteins involved in ammonia metabolism and transport. Furthermore, I have shown that there are significant structural differences between the female and male kidney. Hence, the overall objective of this proposal is to determine the underlying mechanisms of these sex differences in renal ammonia metabolism and to determine the role of these sex differences in physiological relevant disease models. This objective will be evaluated via the following specific aims: 1) determine the role of sex steroid hormones in the regulation of renal ammonia metabolism using a gonadectomy and hormone replacement model; 2) determine the role of sex steroid hormone receptors in the development of sex-dependent differences in ammonia metabolism through the use of kidney-specific AR and ER? deletion; 3) determine the role of sex chromosomes in the regulation of renal ammonia metabolism using the four core genotype model; and, 4) determine the effect of sex on the renal response to conditions of altered ammonia metabolism such as metabolic acidosis. Autumn Harris, DVM, DACVIM (SAIM), is an NIH T32-funded post-doctoral research fellow at the University of Florida College of Medicine. This career development award will provide Dr. Harris with the additional training needed to achieve her goal of becoming an independent investigator, which includes training in the areas of 1) study design and implementation, 2) performance, interpretation, and evaluation of various laboratory techniques and diagnostic tests, 3) statistical methods and interpretation, 4) collaboration with a multidisciplinary and multi-institutional team, 5) grant and manuscript writing. Dr. Harris has developed a comprehensive program including didactic training, practical and laboratory experience, and a strong mentoring and advisory team. The University of Florida College of Medicine will provide a collegial and supportive environment with the equipment, laboratory space, and resources necessary to complete the research and training. At the culmination of this proposal, Dr. Harris will be poised to achieve independence as a researcher with continuing investigation in the field of nephrology and sex differences.